Antibacterial 8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids

ABSTRACT

Antibacterial 8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives of the formula ##STR1## in which Y represents a carboxyl group, a nitrile group, an ester group --COOR 1  or an acid amide group --CONR 2  R 3 , 
     X 1  represents hydrogen nitro, alkyl or halogen 
     X 4  can be hydrogen or halogen, or alkyl, 
     R 4  and R 5 , together with the nitrogen atom to which they are bonded, form a 5- or 6-membered heterocyclic ring which can additionally contain the atoms or groups --O--, --S--, --SO--, --SO 2  --, ##STR2##  as ring members or the group ##STR3##  can also represent a ring system of the structure ##STR4##  which can optionally be substituted on the ring carbons by methyl and pharmaceutically usable hydrates, salts or esters thereof. 
     These compounds have a high antibacterial activity and are therefore suitable as active compounds for human and veterinary medicine.

The present invention relates to new8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acidderivatives, processes for their preparation and antibacterial agentscontaining these compounds.

The new 8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid derivatives of the formula I ##STR5## in which Y represents acarboxyl group, a nitrile group, and ester group --COOR¹ or an acidamide group --CONR² R³,

wherein

R¹ represents alkyl, preferably C₁ -C₄ -alkyl and

R² and R³ independently of one another represent hydrogen or alkyl,preferably C₁ -C₄ -alkyl, and

R³ can also be optionally substituted phenyl,

X¹ represents hydrogen, nitro, alkyl, preferably with 1-3 carbon atoms,or halogen, preferably fluorine,

X⁴ can be hydrogen or halogen, preferably Cl or F, or alkyl, preferablywith 1-3 C atoms, in particular methyl,

R⁴ and R⁵, together with the nitrogen atom to which they are bonded,form a 5- or 6-membered heterocyclic ring which can additionally containthe atoms or groups --O--, --S--, --SO--, --SO₂ --, ##STR6## as ringmembers and which can optionally be mono-, di- or trisubstituted on thecarbon atoms by identical or different substituents from the groupcomprising C₁ -C₄ -alkyl, phenyl and cyclohexyl which are optionallymono-, di- or trisubstituted by chlorine, fluorine, bromine, methyl,phenyl, hydroxyl, methoxy, benzyloxy, nitro or piperidino, 2-thienyl,hydroxyl, alkoxy with one to three carbon atoms, amino, methylamino,ethylamino, aminomethyl, methylaminomethyl and ethylaminomethyl,

wherein

R⁶ represents hydrogen, a branched or straight-chain alkyl, alkenyl oralkynyl group which has 1 to 6 carbon atoms and can optionally besubstituted by one or two hydroxyl, alkoxy, alkylamino or dialkylaminogroups with in each case 1 to 3 carbon atoms for an alkyl radical, thecyano group, the alkoxycarbonyl group with 1 to 4 carbon atoms in thealcohol part, a phenylalkyl group which is optionally substituted in thephenyl radical and has up to 4 carbon atoms in the aliphatic part, aphenacyl radical which is optionally mono- or disubstituted by hydroxyl,methoxy, chlorine or fluorine, or an oxoalkyl radical with up to 6carbon atoms, or furthermore denotes a radical COR⁷ or SO₂ R⁸,

wherein

R⁷ represents hydrogen, straight-chain or branched alkyl which has 1 tocarbon atoms and is optionally substituted by 1 or 2 substituents fromthe series comprising amino, alkoxycarbonyl with 1 to 3 carbon atoms inthe alkyl part, carboxyl, alkoxy with 1 to 3 carbon atoms and halogen,such as chlorine, bromine or fluorine, or represents amino, alkylaminoor dialkylamino with 1 to 5 carbon atoms in the alkyl part, and

R⁸ represents straight-chain or branched alkyl with 1 to 3 carbon atoms,or the group ##STR7## can also represent a ring system of the structure##STR8## which can optionally be substituted on the ring carbons bymethyl, wherein

R⁹ can represent hydrogen, methyl, ethyl, hydroxyethyl, benzyl orp-aminobenzyl, and

pharmaceutically usable hydrates or salts thereof, preferably alkalimetal, alkaline earth metal, silver and guanidinium salts, and theiresters.

The compounds have a high antibacterial activity. They are thereforesuitable as active compounds for human and veterinary medicine. They canalso be used as intermediate products for the preparation of otherbactericides.

Preferred compounds of the formula (I) are those in which

Y represents a carboxyl group, a nitrile group or an ester group--COOR¹,

wherein

R¹ is methyl or ethyl,

X¹ represents fluorine,

X⁴ represents hydrogen,

R⁴ and R⁵, together with the nitrogen atom to which they are bonded, canform a 5- or 6-membered heterocyclic ring which can additionally containan oxygen atom or the groups ##STR9## as a ring member and canoptionally be mono- or disubstituted on the carbon atoms by C₁ -C₂-alkyl, cyclohexyl, phenyl which is optionally substituted by chlorine,fluorine, methyl, phenyl, hydroxyl, methoxy, benzyloxy, nitro orpiperidino, 2-thienyl or hydroxyl,

wherein

R⁶ represents hydrogen, a branched or straight-chain alkyl group whichhas 1 to 3 carbon atoms and can optionally be substituted by one or twohydroxyl groups, a phenacyl radical, an oxalkyl radical with up to 4carbon atoms or a radical COR⁷,

wherein

R⁷ denotes hydrogen or alkyl with one or two carbon atoms, or the group##STR10## can also represent a ring system of the structure ##STR11##wherein R⁹ can represent hydrogen or methyl.

Particularly preferred compounds of the formula I are those in which

Y represents a carboxyl group,

X¹ represents fluorine,

X⁴ represents hydrogen,

R⁴ and R⁵, together with the nitrogen atom to which they are bonded, canform a 5- or 6-membered heterocyclic ring which can additionally containan oxygen atom or the groups ##STR12## as a ring member and canoptionally be mono- or disubstituted on the carbon atoms by C₁ -C₂-alkyl, cyclohexyl, phenyl which is optionally substituted by chlorine,fluorine, methyl, phenyl, hydroxyl, methoxy, benzyloxy, nitro orpiperidino, 2-thienyl or hydroxyl,

wherein

R⁶ represents hydrogen, a straight-chain or branched alkyl group whichhas 1 to 3 carbon atoms and can optionally be substituted by one or twohydroxyl groups, a phenacyl radical, an oxalkyl radical with up to 4carbon atoms or a radical COR⁷,

wherein

R⁷ denotes hydrogen or alkyl with one or two carbon atoms.

The compounds of the formula I according to the invention are obtainedby a process in which quinolonecarboxylic acid derivatives of theformula (II) ##STR13## in which the radicals X¹, X⁴ and Y have theabovementioned meanings and

X² represents halogen, preferably chlorine or fluorine,

are reacted with amines of the formula III ##STR14## in which R⁴ and R⁵have the abovementioned meanings, if appropriate in the presence ofacid-binding agents (Method A).

This process does not necessarily have to be carried out such that R⁴and R⁵ in the amines of the formula (III) already have the final meaningwhich they have in the compounds of the formula (I) according to theinvention. On the contrary, it is also possible to use precursors to theradicals R⁴ and R⁵ in a first step and then to convert these into thefinal form of R⁴ and R⁵ in one or more subsequent reaction steps.

Thus, for example, compounds of the formula (I) according to theinvention can be obtained by a process in which a 7-(1-piperazinyl)compound of the formula (IV) ##STR15## in which X¹, X⁴ and Y have theabovementioned meanings the piperazinyl radical can be substituted onthe carbon atoms in the manner described for R⁴ and R⁵, for example by1, 2 or 3 radicals from the group comprising C₁ -C₄ -alkyl, 2-thienyland optionally substituted cyclohexyl or phenyl,

is reacted with compounds of the formula (V)

    R.sup.6 X                                                  (V)

in which

R⁶ has the abovementioned meaning but cannot be hydrogen and

X denotes fluorine, chlorine, bromine, iodine, hydroxy, acyloxy, ethoxy,phenoxy or 4-nitrophenoxy,

if appropriate in the presence of acid-binding agents (Method B).

In this reaction procedure, the piperazinyl radical in the 7-positioncan thus be introduced in a first reaction step by the method firstmentioned--which leads to the compound (IV) which is already accordingto the invention--and other desired substituents can then be introduced,in this case, for example R⁶, in a subsequent step.

In another embodiment of the process according to the invention,compounds of the formula (I) according to the invention are obtained,for example, by a process in which 7-(1-piperazinyl)quinolonecarboxylicacid derivatives of the formula (IV) in which the piperazinyl radicalcan be substituted on the carbon atoms in the manner already described,for example by 1, 2 or 3 constituents from the group comprising C₁ -C₄-alkyl, 2-thienyl and optionally substituted cyclohexyl or phenyl, arereacted with Michael acceptors of the formula (VI)

    B--CH═CH.sub.2                                         (VI)

in which

B represents CN, CO--R¹⁰ or COOR¹¹,

wherein

R¹⁰ represents methyl or ethyl and

R¹¹ represents methyl, ethyl or n- or i-propyl (Method C).

If, for example, 1-methylpiperazine and7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are used as starting substances in the reaction according to themethod first mentioned, the course of the reaction can be represented bythe following equation: ##STR16##

If, for example, ethyliodide and8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)-3-quinolinecarboxylicacid are used as starting substances in the reaction according to themodified method, the course of the reaction can be represented by thefollowing equation: ##STR17##

The reaction with Michael acceptors with, for example,8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid and methylvinylketone as starting substances can be represented bythe following equation: ##STR18##

The quinolonecarboxylic acids of the formula (II) which can be used asstarting substances in the process according to the invention can beprepared in accordance with the following equation (Process 1).##STR19##

According to this equation, diethyl malonate (2) is acylated with thecorresponding benzoyl fluoride or chloride (1) in the presence ofmagnesium ethylate to give the benzoyl malonate (3) (Organicum, 3rdedition 1964, page 438).

Partial hydrolysis and decarboxylation of (3) in an aqueous medium withcatalytic amounts of sulphuric acid or p-toluenesulphonic acid gives agood yield of the ethyl benzoylacetate (4), which is converted into theethyl 3-ethoxyacrylate (5) with triethyl orthoformate/acetic anhydride.The reaction of (5) with cyclopropylamine in a solvent, such as, forexample methylene chloride, alcohol, chloroform, cyclohexane or toluene,leads to the desired intermediate product (6) in a slightly exothermicreaction.

The cyclization reactions (6)→(7) are carried out in a temperature rangefrom about 602° to 300° C., preferably 80° to 180° C.

Diluents which can be used are dioxane, dimethyl sulphoxide,N-methylpyrrolidone, sulpholane, hexamethylphosphoric acid triamide and,preferably, N,N-dimethylformamide.

Possible acid-binding agents for this reaction stage are potassiumtert.-butanolate, butyl-lithium, lithiumphenyl, phenylmagnesium bromide,sodium methylate, sodium hydride and sodium or potassium carbonate, andparticularly preferably potassium fluoride or sodium fluoride. It may bebeneficial to use an excess of 10 mol % of base.

The hydrolysis of the esters (7) carried out in the last step to givethe corresponding carboxylic acids can be effected under the customaryacid or basic conditions.

The 2,4-dichloro-3-cyano-5-fluorobenzoyl chloride used as the startingsubstance for this synthesis route is obtainable as follows:

(a) 2,4-dichloro-5-fluoro-3-nitro-benzoic acid

40 ml of concentrated nitric acid are added dropwise to 34 ml ofconcentrated sulphuric acid, while cooling with ice and stirring. 20.9 gof 2,4-dichloro-5-fluorobenzoic acid are introduced in portions intothis nitrating mixture, whereupon the temperature rises to 45°-50° C.The mixture is then heated at 90°-100° C. for a further 3 hours, themixture is cooled to room temperature and poured onto 350 ml ofice-water and the precipitate is filtered off with suction and washedwith water. The moist crude product is dissolved in 30 ml of hotmethanol and 150 ml of H₂ O are added to the solution. The precipitateis filtered off cold with suction, washed with CH₃ OH/H₂ O and dried invacuo at 80° C. 21.2 g of crude 2,4-dichloro-5-fluoro-3-nitro-benzoicacid are obtained. It is sufficiently pure for further reactions.

Melting point: 192° C. (from toluene/petroleum ether).

(b) 3-Amino-2,4-dichloro-5-fluoro-benzoic acid

254 g (1 mol) of 2,4-dichloro-5-fluoro-3-nitrobenzoic acid arehydrogenated in 1.8 l of ethanol in the presence of 60 g of Raney nickelat 11°-20° C. under 10 bar of hydrogen, the mixture is filtered and thefiltrate is concentrated in vacuo. The paste-like residue is kneadedwith water and the product which has crystallized out is filtered offwith suction, washed with water and dried.

Yield: 197 g (88% of theory)

Melting point: 175°-177° C., from toluene: 184°-187° C.

(c) 2,4-Dichloro-3-cyano-5-fluoro-benzoic acid

56 g of 3-amino-2,4-dichloro-5-fluoro-benzoic acid are diazotized in 700ml of half-concentrated sulphuric acid by addition of 2.5 molar NaNO₂solution at 0°-5° C. Excess nitrite is destroyed by addition of urea.The diazonium salt solution is then added dropwise to a mixture of 27 gof CuCN and 200 ml of 4.5 molar NaCN solution at 0° C. After the end ofthe dropwise addition, the mixture is heated at 80° C. for one hour. Itis then cooled and the solid is isolated and dried. The solid (64.3 g)is boiled up with toluene. The insoluble material is filtered off andthe solvent is largely evaporated off. On cooling, the acid crystallizesout.

Yield: 44 g

Melting point: 188°-190° C.; recrystallization again from toluene givesa melting point of 203°-205° C.

(d) 2,4-Dichloro-3-cyano-5-fluoro-benzoic acid chloride

25 g of 2,4-dichloro-3-cyano-5-fluoro-benzoic acid and 30 ml of thionylchloride are boiled until the evolution of gas has ended. The excessthionyl chloride is then stripped off in vacuo. 25.6 g of acid chlorideof melting point 69°-72° C. remain.

The amines (III) used as starting substances are known or can beobtained by processes which are known from the literature, U.S. Pat. No.4,166,188 and J. Med. Chem. 26, 1116 (1983). The corresponding2-cyclohexylpiperazines are obtained from the 2-arylpiperazines bycatalytic hydrogenation: for example 2-cyclohexylpiperazine (waxy,melting point 71°-73° C.). Examples which may be mentioned are:morpholine, piperidine, thiomorpholine, pyrrolidone, piperazine,N-methylpiperazine, N-ethylpiperazine, N-(2-hydroxyethyl)-piperazine,N-formylpiperazine, 2-methylpiperazine, 1,2-dimethylpiperazine, cis- andtrans-2,5-dimethylpiperazine, 2-propylpiperazine, 2-isopropylpiperazine,2-isobutylpiperazine, 2-piperazinone, 1-methyl-2-piperazinone,1-ethyl-2-piperazinone, 2-cyclohexyl-1-piperazine, 2-phenylpiperazine,2-(4-chlorophenyl)-piperazine, 2-(4-fluorophenyl)-piperazine,2-(4-bromophenyl)-piperazine, 2-(4-methylphenyl)piperazine,2-(4-biphenyl)-piperazine, 2-(4-methoxyphenyl)piperazine,2-(4-benzyloxyphenyl)-piperazine, 2-(4-hydroxyphenyl)-piperazine,2-(4-nitrophenyl)-piperazine, 2-(3-nitrophenyl)-piperazine,2-(4-piperidinophenyl)-piperazine, 2-(3,4-dimethoxyphenyl)-piperazine,2-(3,4,5-trimethoxyphenyl)-piperazine,2-(3-dimethoxy-6-methyl)-piperazine, 2-(2-thienyl)-piperazine,3-aminopyrrolidine, 2,5-diazabicyclo12.2.1]heptane dihydrochloride,2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride,8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride,3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride,3-(4-aminobenzyl)-3,8-diazabicyclo[3.2.1]octane,3-ethyl-3,8-diazabicyclo[3.2.1]octane,3-benzyl-3,8-diazabicyclo[3.2.1]octane and2-methyl-2,5-diazabicyclo[2.2.2]octane dihydrochloride.

The compounds of the formula (V) used as starting substances are known.Examples which may be mentioned are: methyl iodide, methyl bromide,ethyl iodide, ethyl bromide, ethyl chloride, 2-hydroxyethyl chloride,3-hydroxypropyl chloride, 4-hydroxybutyl chloride, n-propyl bromide,i-propyl iodide, n-butyl bromide, i-butyl bromide, sec.-butyl chloride,n-pentyl chloride, 3-methylbutyl chloride, n-hexyl bromide, formicacid-acetic acid anhydride, acetic anydride, propionic anhydride, acetylchloride, chloroacetyl chloride, dichloroacetyl chloride, bromoacetylbromide, butyryl chloride, 4-chlorobutyryl chloride, isobutyrylchloride, N-(tert.-butoxycarbonyl)-glycine 4-nitrophenyl ester,N-(tert.-butoxycarbonyl)-L-alanine 4-nitrophenyl ester,N-(tert.-butoxycarbonyl)-L-leucine 4-nitrophenyl ester,N-(tert.-butoxycarbonyl)-L-valine 4-nitrophenyl ester,3-methoxypropionyl chloride, methylchlorocarbonate,ethylchlorocarbonate, n-butylchlorocarbonate, diethylcarbonate, cyanogenchloride, diphenylcarbonate, cyanogen bromide, dimethylcarbamoylchloride, methanesulphonyl chloride, ethanesulphonyl chloride,propane-1-sulphonyl chloride and formic acid.

The compounds of the formula (VII) which can be used according to theinvention are known. Examples which may be mentioned are: acrylonitrile,methylvinylketone, - methylacrylate and ethylacrylate.

The reaction of (II) with (III) according to Method A is preferablycarried out in a diluent, such as dimethyl sulphoxide,N,N-dimethylformamide, hexamethylphosphoric acid trisamide, sulpholane,water, an alcohol, such as methanol, ethanol, N-propanol, isopropanol orglycolmonomethylether, or pyridine. Mixtures of these diluents can alsobe used.

All the customary organic and inorganic acid-binding agents can be usedas the acid-binding agent. These include, preferably, the alkali metalhydroxides, alkali metal carbonates, organic amines and amidines.Specific examples which may be mentioned as particularly suitable are:triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or excess amine (III).

The reaction temperatures can be varied within a substantial range. Thereaction is in general carried out between about 20° and 200° C.,preferably between 80° and 180° C.

The reaction can be carried out under normal pressure or under increasedpressure. It is in general carried out under pressures between about 1and about 100 bar, preferably between 1 and 10 bar.

In carrying out the process according to the invention, 1 to 15 mol,preferably 1 to 6 mol of the amine (III) are employed per mole of thecarboxylic acid (II).

The reaction of (IV) with (V) is preferably carried out with a diluent,such as dimethyl sulphoxide, dioxane, N,N-dimethylformamide,hexamethylphosphoric acid trisamide, sulpholane, water, an alcohol, suchas methanol, ethanol, n-propanol, isopropanol or glycolmonomethylether,or pyridine. Mixtures of these diluents can also be used.

Acid-binding agents which can be used are all the customary inorganicand organic acid-binding agents. These include, preferably, the alkalimetal hydroxides, alkali metal carbonates, organic amides and amidines.Specific examples which may be mentioned as particularly suitable are:triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO) or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

The reaction temperatures can be varied within a substantial range. Thereaction is in general carried out between about 20° and about 180° C.,preferably between 40° and 110° C.

The reaction can be carried out under normal pressure, but also underincreased pressure. It is in general carried out under pressures betweenabout 1 and about 100 bar, preferably between 1 and 10 bar.

In carrying out the process according to the invention by Method B, 1 to4 mol, preferably 1 to 1.5 mol, of the compound (V) are employed per 1mol of the compound (IV).

The reaction of (IV) with (VI) (Method C) is preferably carried out in adiluent, such as dioxane, dimethyl sulphoxide, N,N-dimethylformamide,methanol, ethanol, isopropanol, n-propanol, glycolmonomethylether ormixtures of these diluents.

The reaction temperatures can be varied within a substantial range. Thereaction is in general carried out between about 20° C. and about 150°C., preferably between 50° C. and 100° C.

The reaction can be carried out under normal pressure, but also underincreased pressure. It is in general carried out under pressures ofbetween about 1 and about 100 bar, preferably between 1 and 10 bar.

In carrying out the process according to the invention by Method C, 1 to5 mol, preferably 1 to 2 mol, of the compound (VI) are employed per molof the compound (IV).

New active compounds which may be mentioned specifically, in addition tothe compounds mentioned in the examples, are:8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-morpholinyl)-4-oxo-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-phenyl-1-piperazinyl)-3-quinolinecarboxylicacid,6-chloro-8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-oxo(4-thiomorpholinyl)-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-7(1-piperidinyl)-4-oxo-3-quinolinecarboxylicacid,7-(3-amino-1-pyrrolidinyl)-8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperidinyl)-3-quinoline-carboxylicacid,8-cyano-1-cyclopropyl-7-(3-ethylamino-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-7(3-ethylaminomethyl-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-7(-2,5-diazabicyclo12.2.1]oct-5-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-7-(3,8-diazabicyclo[[3.2.1]oct-3-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-7(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)4-oxo-3-quinolinecarboxylicacid, 6-chloro-8-cyano-1-cyclopropyl-7-(3,8-diazabicyclo[3.2.1oct-3-yl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,6-chloro-8-cyano-1-cyclopropyl-1,4-dihydro-7-(5-methyl-2,5-diazabicyclo[2.2.1]-hept-2-yl)-4-oxo-3-quinolinecarboxylicacid, 8-cyano-1-cyclopropyl-1,4-dihydro-7-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-6- nitro-4-oxo-3-quinolinecarboxylic acid,8-cyano-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-7(1-piperazinyl)-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-1,4-dihydro-7-(3-methyl-1-piperazinyl)-6-nitro-4-oxo-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-7-(3-phenyl-1-piperazinyl)-3-quinolinecarboxylicacid,6-(3-amino-1-pyrrolidinyl)-8-cyano-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-5,6-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-5,6-difluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid,5-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid,5-chloro-8-cyano-1-cyclopropyl-7-(3,8-diazabicyclo[3.2.1]-oct-3-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,5-chloro-8-cyano-1-cyclopropyl-7-(3-ethylamino-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid,7-(3-amino-1-pyrrolidinyl)-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-7-(3-phenyl-1-piperazinyl)-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-7-(3,8-diazabicyclo[3.2.1]oct-3-yl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-7-(3-ethylamino-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-1,4-dihydro-5,6-dimethyl-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid, and8-cyano-1-cyclopropyl-1,4-dihydro-5,6-dimethyl-4-oxo-7-(1-pyrrolidinyl)-3-quinolinecarboxylicacid.

The following examples illustrate the invention.

EXAMPLE 1 ##STR20##7-Chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

1.2 g of magnesium filings are stirred into 3 ml of ethanol and 0.3 mlof CCl₄ and, when the reaction has started, 7 g of diethylmalonate in 5ml of EtOH and 18 ml of toluene are added dropwise at 50°-60° C. Themixture is subsequently stirred at this temperature for 1 hour andcooled to -5° to -10° C., a solution of 11 g of2,4-dichloro-3-cyano-5-fluorobenzoyl chloride in 5 ml of toluene isadded dropwise and the mixture is stirred at 0° C. for a further hourand left to stand at room temperature overnight. It is then cooled and20 ml of water and 3 ml of concentrated H₂ SO₄ are added. The organicphase is separated off, the aqueous phase is extracted with toluene andthe combined organic phases are washed with saturated NaCl solution,dried with sodium sulphate and concentrated.

The residue (16.7 g) is boiled with 20 ml of water and 0.35 g ofp-toluenesulphonic acid for 4.5 hours. The mixture is then extractedwith CH₂ Cl₂ and the organic phase is washed with sodium chloridesolution, dried over sodium sulphate and concentrated. 11.6 g of residueremain.

The residue is heated at 150° C. together with 8.7 g of orthoformate and9.8 g of acetic anhydride for two hours and the mixture is subsequentlyconcentrated at 120°-130° C., first under atmospheric pressure and thenunder a high vacuum. 12.7 g of ethyl2-(2,4-dichloro-3-cyano-5-fluorobenzoyl)-3-ethoxyacrylate are obtainedas an oil.

2.5 g of cyclopropylamine are added to the 12.7 g of this compound in 30ml of ethanol, while cooling with ice, and the mixture is stirred atroom temperature for 2 hours. Thereafter, it is stirred with 30 ml ofwater and cooled in ice and the solid which has precipitated out isseparated off, washed with water and dried.

11.8 g of ethyl2-(2,4-dichloro-3-cyano-5-fluoro-benzoyl)-3-cyclopropylaminoacrylate ofmelting point 65°-67° C. are obtained.

41.2 g of this compound and 13.6 g of KOtBu are stirred in 500 ml ofdioxane at room temperature for 24 hours. Water is then added and themixture is extracted with CH₂ Cl₂.

The organic phase is washed, dried over sodium sulphate andconcentrated. The residue which remains is stirred with isopropanol. Thesolid obtained is isolated and dried. 18.0 g of ethyl7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylateof melting point 162°-165° C. are obtained.

1 g of this compound is heated at 140°-145° C. together with 3.5 ml ofacetic acid, 3 ml of water and 0.3 ml of sulphuric acid for 4 hours. Themixture is then diluted with water and the solid is isolated. 0.7 g ofthe title compound of melting point 281°-282° C. are obtained.

EXAMPLE 28-Cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)-3-quinolinecarboxylicacid ##STR21##

0.5 g of the product from Example 1 and 0.42 g of piperazine are boiledin 8 ml of dioxane for 3 hours. The mixture is then concentrated invacuo and 8 ml of water are added to the residue. The solution formed isrendered neutral with HCl and the solid which has precipitated outisolated, washed and dried.

Yield: 0.4 g of the title compound

Melting point: >300° C.

EXAMPLE 38-Cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-7(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid ##STR22##

0.5 g of the product from Example 1 and 0.48 g of N-methylpiperazine areboiled in 8 ml of dioxane for 3 hours. The mixture is then concentratedin vacuo, water is added to the residue and the solution formed isrendered neutral. The solid which has precipitated out is isolated,washed and dried.

Yield: 0.5 g of the title compound

Melting point: 264°-265° C.

EXAMPLE 48-Cyano-1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid ##STR23##

0.5 g of the product from Example 1 and 0.55 g of N-ethylpiperazine areboiled in 8 ml of dioxane for 3 hours. The mixture is then concentratedin vacuo. The residue is taken up in water and rendered neutral. Themixture is extracted with methylene chloride and the organic phase isseparated off, dried over sodium sulphate and concentrated. 0.5 g of thetitle compound of melting point >300° C. remains.

EXAMPLE 58-Cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid ##STR24##

0.5 g of the product from Example 1 and 0.48 g of 2-methylpiperazine areboiled in 8 ml of dioxane for 3 hours. The mixture is then concentratedin vacuo and water is added to the residue.

1 N HCl is added until the solution is neutral. The solid which hasprecipitated out is filtered off with suction and dried. 0.4 g of thetitle compound with a melting point of >300° C. is obtained.

EXAMPLE 68-Cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-pyrrolidinyl)-3-quinolinecarboxylicacid ##STR25##

3.05 g of the product from Example 1 and 2.5 ml of pyrrolidine areboiled in 50 ml of dioxane for 3 hours. The mixture is concentrated invacuo and the residue is taken up in water. The mixture is renderedneutral with 1N HCl. The solid which has precipitated out is filteredoff with suction, dried and stirred with acetonitrile. 1.8 g of thetitle compound with a melting point of 274°-276° C. are obtained.

Example of a tablet according to the invention

Each tablet contains:

    ______________________________________                                        Compound of Example 5    583.0 mg                                             Microcrystalline cellulose                                                                             55.0 mg                                              Maize starch             72.0 mg                                              Poly-(1-vinyl-2-pyrrolidone) insoluble                                                                 30.0 mg                                              Hughly dispersed silicon dioxide                                                                       5.0 mg                                               Magnesium stearate       5.0 mg                                                                        750.0 mg                                             ______________________________________                                    

The lacquer shell contains:

    ______________________________________                                        Poly-(O--hydroxypropyl-O--methyl)-cellulose                                                             6.0 mg                                              15 cup                                                                        Macrogol 4000 recommended INN                                                                           2.0 mg                                              Polyethyleneglycol (DAB)                                                      Titanium-(IV) oxide       2.0 mg                                                                        10.0 mg                                             ______________________________________                                    

The compounds according to the invention exhibit a broad antibacterialspectrum against Gram-positive and Gram-negative germs, in particularagainst Enterobacteriaceae --above all against those which are resistantto various antibiotics, such as, for example, penicillins,cephalosporins, aminoglycosides, sulphonamides andtetracyclines--coupled with a low toxicity.

These useful properties enable them to be used as chemotherapeuticactive compounds in medicine and as substances for the preservation ofinorganic and organic materials, in particular all types of organicmaterials, for example polymers, lubricants, paints, fibers, leather,paper and wood, and foodstuffs and water.

The compounds according to the invention are active against a very broadspectrum of microorganisms. With the aid of the compounds, Gram-negativeand Gram-positive bacteria and bacteria-like microorganisms can becombated and the diseases caused by these pathogens can be prevented,alleviated and/or cured.

The compounds according to the invention are particularly active againstbacteria and bacteria-like microorganisms. They are thereforeparticularly suitable in human and veterinary medicine for theprophylaxis and chemotherapy of local and systemic infections caused bythese pathogens.

For example, local and/or systemic diseases which are caused by thefollowing pathogens or by mixtures of the following pathogens can betreated and/or prevented: Gram-positive cocci, for example Staphylococci(Staph. aureus and Staph. epidermidis) and Streptococci (Strept.agalactiae, Strept. faecalis, Strept. pneumoniae and Strept. pyogenes);Gram-negative cocci (Neisseria gonorrhoaea) and Gram-negative rod-shapedbacilli, such as Enterobacteriaciae, for example Escherichia coli,Haemophilus influenzae, Citrobacter (Citrob. freundii and Citrob.divernis), Salmonella and Shigella; and furthermore Klebsiellae (Klebs.pneumoniae and Klebs. oxytoca), Enterobacter (Ent. aerogenes and Ent.agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr.mirabilis, Pr. rettgeri and Pr. vulgaris), Providencia, Yersinia and thegenus Acinetobacter. The antibacterial spectrum moreover includes thegenus Pseudomonas (Ps. aeruginosa and Ps. maltophilia) and strictlyanaerobic bacteria, such as, for example, Bacteroides fragilis,representatives of the genus Peptococcus, Peptostreptococcus and thegenus Clostridium; and furthermore Mycoplasma (M. pneumoniae, M. hominisand M. urealyticum) and mycobacteria, for example Mycbbacteriumtuberculsis.

The above list of pathogens is purely by way of example and is in no wayto be interpreted as limiting. Examples which may be mentioned ofdiseases which can be caused by the pathogens or mixed infectionsmentioned and can be prevented, alleviated or cured by the compoundsaccording to the invention are: infectious diseases in humans, such as,for example, otitis, pharyngitis, pneumonia, peritonitis,pyelonephritis, cystitis, endocarditis, systemic infections, bronchitis(acute and chronic), septic infections, diseases of the upperrespiratory tract, diffuse panbronchiolitis, pulmonary emphysema,dysentery, enteritis, liver abscesses, urethritis, prostatitis,epididymitis, gastrointestinal infections, bone and joint infections,cystic fibrosis, skin infections, postoperative wound infections,abscesses, phlegmons, wound infections, infected burns, burn wounds,infections in the oral region, infections following dental operations,osteomyelitis, septic arthritis, cholecystitis, peritonitis withappendicitis, cholangitis, intraabdominal abscesses, pancreatitis,sinusitis, mastoiditis, mastitis, tonsillitis, typhus, meningitis andinfections of the nervous system, salpingitis, endometritis, genitalinfections, pelveoperitonitis and eye infections.

Bacterial infections in other species, as well as in humans, can also betreated. Examples which may be mentioned are:

Pigs: coli diarrhoea, enterotoxaemia, sepsis, dysentery, salmonellosis,mastitis-metritis-agalactia syndrome and mastitis;

Ruminants (cattle, sheep, goats): diarrhoea, sepsis, bronchopneumonia,salmonellosis, pasteurellosis, mycoplasmosis and genital infections;

Horses: various types of bronchopneumonia, joint ill, puerperal andpost-puerperal infections and salmonellosis;

Dogs and cats: bronchopneumonia, diarrhoea, dermatitis, otitis, urinarytract infections and prostatitis; and

Poultry (chickens, turkeys, quail, pigeons, ornamental birds andothers): mycoplasmosis, E. coli infections, chronic respiratory tractinfections, salmonellosis, pasteurellosis and psittacosis.

Bacterial diseases can also be treated in the breeding and rearing ofuseful and ornamental fish, the antibacterial spectrum extending beyondthe abovementioned pathogens to further pathogens, such as, for example,Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothrix,Corynebacteria, Borrelia, Treponema, Nocardia, Rickettsia and Yersinia.

The present invention includes pharmaceutical formulations which, inaddition to non-toxic inert pharmaceutically suitable excipients,contain one or more compounds according to the invention or consist ofone or more active compounds according to the invention, and processesfor the preparation of these formulations.

The present invention also includes pharmaceutical formulations indosage units. This means that the formulations are present in the formof individual parts, for example tablets, dragees, capsules, pills,suppositories and ampoules, the active compound content of whichcorresponds to a fraction or a multiple of an individual dose. Thedosage units can contain, for example, 1, 2, 3 or 4 individual doses ora 1/2, a 1/3 or a 1/4 of an individual dose. An individual dosepreferably contains the amount of active compound which is given in oneadministration and usually corresponds to a whole, one half, one thirdor one quarter of a daily dose.

By non-toxic inert pharmaceutically suitable excipients there are to beunderstood all types of solid, semi-solid or liquid diluents, fillersand formulation auxiliaries.

Preferred pharmaceutical formulations which may be mentioned aretablets, dragees, capsules, pills, granules, suppositories, solutions,suspensions and emulsions, pastes, ointments, gels, creams lotions,powders and sprays.

Tablets, dragees, capsules, pills and granules can contain the activecompound or compounds, in addition to the customary excipients, such as(a) fillers and extenders, for example starches, lactose, sucrose,glucose, mannitol and silicic acid, (b) binders, for examplecarboxymethylcellulose, alginates, gelatins and polyvinylpyrrolidone,(c) humectants, for example glycerol, (d) disintegrating agents, forexample agar-agar, calcium carbonate and sodium carbonate, (e) solutionretarders, for example paraffin, and (f) absorption accelerators, forexample quaternary ammonium compounds, (g) wetting agents, for examplecetyl alcohol and glycerol monostearate, (h) adsorbents, for examplekaolin and bentonite, and (i) lubricants, for example talc, calciumstearate and magnesium stearate and solid polyethyleneglycols ormixtures of the substances listed under (a) to (i).

The tablets, dragees, capsules, pills and granules can be provided withthe customary coatings and shells, optionally containing opacifyingagents, and can also be of such composition that they release the activecompound or compounds only or preferentially in a certain part of theintestinal tract, if appropriate in a delayed manner, examples ofembedding compositions which can be used being polymeric substances andwaxes.

The active compound or compounds can also be in microencapsulated form,if appropriate with one or more of the abovementioned excipients.

Suppositories can contain, in addition to the active compound orcompounds, the customary water-soluble or water-insoluble excipients,for example polyethylene glycols, fats, for example cacao fat, andhigher esters (for example C₁₄ -alcohol with C₁₆ -fatty acid), ormixtures of these substances.

Ointments, pastes, creams and gels can contain, in addition to theactive compound or compounds, the customary excipients, for exampleanimal and vegetable fats, waxes, paraffins, starch, tragacanth,cellulose derivatives, polyethyleneglycols, silicones, bentonites,silicic acid, talc and zinc oxide, or mixtures of these substances.

Powders and sprays can contain, in addition to the active compound orcompounds, the customary excipients, for example lactose, talc, silicicacid, aluminium hydroxide, calcium silicate and polyamide powder, ormixtures of these substances. Sprays can additionally contain thecustomary propellants, for example chlorofluorohydrocarbons.

Solutions and emulsions can contain, in addition to the active compoundor compounds, the customary excipients, such as solvents, solubilizingagents and emulsifiers, for example water, ethyl alcohol, isopropylalcohol, ethylcarbonate, ethylacetate, benzyl alcohol, benzyl benzoate,propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, inparticular cotton seed oil, groundnut oil, maize germ oil, olive oil,castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfurylalcohol, polyethylene glycol and fatty acid esters of sorbitan, ormixtures of these substances.

For parenteral administration, the solutions and emulsions can also bein a sterile form which is isotonic with blood.

Suspensions can contain, in addition to the active compound orcompounds, the customary excipients, such as liquid diluents, forexample water, ethyl alcohol or propylene glycol, suspending agents, forexample ethoxylated isostearyl alcohols, polyoxyethylene sorbitol andsorbitan esters, microcrystalline cellulose, aluminum metahydroxide,bentonite, agar-agar and tragacanth, or mixtures of these substances.

The formulation forms mentioned can also contain coloring agents,preservatives and additives which improve the smell and taste, forexample peppermint oil and eucalyptus oil, and sweeteners, for examplesaccharin.

The therapeutically active compounds should preferably be present in theabovementioned pharmaceutical formulations in a concentration of about0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.

In addition to the compounds according to the invention, theabovementioned pharmaceutical formulations can also contain otherpharmaceutical active compounds.

The abovementioned pharmaceutical formulations are prepared in acustomary manner by known methods, for example by mixing the activecompound or compounds with the excipient or excipients.

The formulations mentioned can be administered to humans and animalseither orally, rectally, parenterally (intravenously, intramuscularly orsubcutaneously), intracisternally, intravaginally, intraperitoneally orlocally (powders, ointments and drops) and for the therapy of infectionsin hollow spaces and body cavities. Suitable formulations are injectionsolutions, solutions and suspensions for oral therapy and gels, infusionformulations, emulsions, ointments or drops. Ophthalmological anddermatological formulations, silver salts and other salts, ear drops,eye ointments, powders or solutions can be used for local therapy. Inthe case of animals, intake can also be via the feed or drinking waterin suitable formulations. It is furthermore possible to use gels,powders, dusting agents, tablets, sustained release tablets, premixes,concentrates, granules, pellets, boli, capsules, aerosols, sprays andinhalates on humans and animals. The compounds according to theinvention can furthermore be incorporated into other carrier materials,such as, for example, plastics (chains of plastics for local therapy),collagen or bone cement.

In general, it has proved advantageous both in human and in veterinarymedicine to administer the active compound or compounds according to theinvention in total amounts of about 0.5 to about 500, preferably 5 to100 mg/kg of body weight every 24 hours, if appropriate in the form ofseveral individual doses, in order to achieve the desired results. Anindividual dose preferably contains the active compound or compoundsaccording to the invention in amounts of about 1 to about 80, inparticular 3 to 30 mg/kg of body weight. However, it may be necessary todeviate from the dosages mentioned, and in particular to do so as afunction of the nature and body weight of the subject to be treated, thenature and severity of the disease, the nature of the formulation and ofthe administration of the medicament and the period or interval withinwhich administration takes place.

Thus in some cases it may suffice to manage with less than theabovementioned amount of active compound, whilst in other cases theabovementioned amount of active compound must be exceeded. Theparticular optimum dosage and mode of administration required for theactive compounds can easily be determined by any expert on the basis ofhis specialist knowledge.

The new compounds can be administered together with the feed or withfeed formulations or with the drinking water in the customaryconcentrations and formulations. An infection by Gram-negative orGram-positive bacteria can thereby be prevented, alleviated and/or curedand a promotion in growth and an improvement in feed utilization canthereby be achieved.

What is claimed is:
 1. An8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acidderivative of the formula ##STR26## in which Y represents carboxyl,nitrile, --COOR¹ or --CONR² R³,wherein R¹ represents alkyl, and R² andR³ each independently represent hydrogen or alkyl, and R³ represents anunsubstituted phenyl, X¹ represents hydrogen, nitro, alkyl, or halogen,X⁴ represents hydrogen or halogen or alkyl, R⁴ and R⁵, together with thenitrogen atom to which they are bonded, form 6-membered heterocyclicring which additionally has the group ##STR27## as a ring member andwhich is unsubstituted or mono-, di- or trisubstituted on the carbonatoms by identical or different substituents said substituents being C₁-C₄ -alkyl, phenyl and cyclohexyl and said substituents beingunsubstituted or mono-, di-or trisubstituted by chlorine, fluorine,bromine, methyl, phenyl, hydroxyl, methoxy, benzloxy, nitro orpiperidino, 2-thienyl, hydroxy, alkoxy with one to three carbon atoms,amino, methylamino, ethylamino, aminomethyl, methylaminomethyl andethylaminomethyl,wherein R⁶ represents hydrogen, a branched orstraight-chain alkyl, alkenyl or alkynyl which has 1 to 6 carbon atomsand is unsubstituted or substituted by one or two hydroxyl, alkoxy,alkylamino or dialkylamino groups with in each case 1 to 3 carbon atomsin the alkyl radical, cyano, alkoxycarbonyl with 1 to 4 carbon atoms inthe alcohol part, phenylalkyl which is unsubstituted and has up to 4carbon atoms in the aliphatic part, phenacyl which is unsubstituted ormono- or disubstituted by hydroxyl, methoxy, chlorine or fluorine, or anoxoalkyl radical with up to 6 carbon atoms, or furthermore denotes aradical COR⁷ or SO₂ R⁸,wherein R⁷ represents hydrogen, straight-chain orbranched alkyl which has 1 to 4 carbon atoms and is unsubstituted orsubstituted by 1 or 2 substituents said substituents being amino,alkyoxycarbonyl with 1 to 3 carbon atoms in the alkyl part, carbonxyl,alkoxy with 1 to 3 carbon atoms and halogen, or amino, alkylamino ordialkylamino with 1 to 5 carbon atoms in the alkyl part, and R⁸represents straight-chain or branched alkyl with 1 to 3 carbon atoms,and pharmaceutically acceptable hydrates or salts thereof, and theiresters.
 2. A compound according to claim 1, in whichY representscarboxyl, nitrile or an ester group --COOR¹,wherein R¹ is methyl orethyl, X¹ represents fluorine, X⁴ represents hydrogen, R⁴ and R⁵,together with the nitrogen atom to which they are bonded, form a6-membered heterocyclic ring which additionally has the group ##STR28##as a ring member and which is unsubstituted or mono- or disubstituted onthe carbon atoms by C₁ -C₂ -alkyl, cyclohexyl, phenyl which isunsubstituted or substituted by chlorine, fluorine, methyl, phenyl,hydroxyl, methoxy, benzyloxy, nitro or piperidino, 2-thienyl orhydroxyl,wherein, R⁶ represents hydrogen, a branched or straight-chainalkyl group which has 1 to 3 carbon atoms and is unsubstituted orsubstituted by one or two hydroxyl groups, phenacyl, oxalkyl with up to4 carbon atoms or a radical COR⁷,wherein, R⁷ denotes hydrogen or alkylwith one or two carbon atoms.
 3. A compound according to claim 1, inwhichY represents carboxyl group, X¹ represents fluorine, X⁴ representshydrogen, R⁴ and R⁵, together with the nitrogen atom to which they arebonded, form a 6-membered heterocyclic ring which additionally has thegroup ##STR29## as a ring member and which is unsubstituted or mono- ordisubstituted on the carbon atoms by C₁ -C₂ -alkyl, cyclohexyl, phenylwhich is unsubstituted or substituted by chlorine, fluorine, methyl,phenyl, hydroxyl, methoxy, benzyloxy, nitro or piperidino, 2-thienyl orhydroxyl,wherein, R⁶ represents hydrogen, a straight-chain or branchedalkyl group which has 1 to 3 carbon atoms and is unsubstituted orsubstituted by one or two hydroxyl groups, phenacyl, oxalkyl with up to4 carbon atoms or a radical COR⁷,wherein, R⁷ denotes hydrogen or alkylwith one or two carbon atoms.
 4. A compound according to claim 1,whereinR¹ represents C₁ -C₄ -alkyl and R² and R³ each independentlyrepresent hydrogen or C₁ -C₄ -alkyl, X¹ represents hydrogen, nitro, C₁-C₃ -alkyl or halogen, X⁴ represents hydrogen or halogen or C₁ -C₃-alkyl.
 5. A compound according to claim 1, selected from the groupconsistingofcyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-phenyl-1-piperazinyl)-3-quinolinecarboxylicacid, 6-chloro-8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid,8-cyano-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-7(1-piperazinyl)-3-quinolinecarboxylicacid,8-cyano-1-1,4-dihydro-7-(3-methyl-1-piperazinyl)-6-nitro-4-oxo-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-7-(3-phenyl-1-piperazinyl)-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-5,6-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-5,6-difluoro-1,4-dihyro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid,5-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid,8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid,8-cycano-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-7-(3-phenyl-1-piperazinyl)-3-quinolinecarboxylicacid, and8-cyano-1-cyclopropyl-1,4-dihydro-5,6-dimethyl-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid.
 6. An antibacterial composition comprising an antibacteriallyeffective amount of a compound according to claim 1 and apharmaceutically acceptable excipient.
 7. A unit dosage form of acomposition according to claim
 6. 8. A method of combating bacterialwhich comprises administering to a patient in need thereof an amounttherefor of a compound according to claim 1.